Atrial Fibrillation in Aging and Frail Mice
Hailey J. Jansen, Motahareh Moghtadaei, Sara A. Rafferty, Robert A. Rose
Abstract
Background: Atrial fibrillation is prevalent in aging populations; however, not all individuals age at the same rate. Rather, health status during aging can vary from fit to frail. Frailty can be quantified using a frailty index (FI). Natriuretic peptides modulate atrial function in part by activating NP (natriuretic peptide) receptor C (NPR-C). The impacts of NPR-C on atrial structure and arrhythmogenesis in aging and as a function of frailty are unknown. Methods: Frailty was measured in aging wildtype and NPR-C knockout (NPR-C − /− ) mice. Atrial structure and function were studied using intracardiac electrophysiology in anesthetized mice, high-resolution optical mapping in intact atrial preparations, histology, and molecular biology. Results: NPR-C −/− mice had a shortened lifespan and more rapidly became frail compared with wildtype mice. Atrial fibrillation burden and P wave duration were increased in older versus younger wildtype mice and further increased in older NPR-C −/− mice; however, there was substantial variability among age groups and genotypes. P wave duration was strongly correlated with FI score regardless of age or genotype. Optical mapping of the atria demonstrated reduced conduction velocity and changes in action potential duration that were also graded by FI score. Atrial fibrosis was increased in aged and NPR-C −/− mice and was strongly correlated with FI score. Atrial fibrosis was associated with changes in expression of profibrotic genes, including MMPs (matrix metalloproteinases), TIMPs (tissue inhibitors of metalloproteinases), and TGFβ (transforming growth factor β). Gene expression changes were also correlated with FI scores. Conclusions: NPR-C plays an essential role in the aging-dependent decline in health status as well as alterations in atrial function and arrhythmogenesis. Frailty assessment is a highly effective approach for identifying age-dependent heterogeneity in atrial structure and function, including in the setting of shortened lifespan because of loss of NPR-C.